Viral infections of the central nervous system (CNS) are associated with an increased risk for seizures, status epilepticus (SE), and the development of chronic epilepsy. We recently described a novel animal model of viral-induced epilepsy. Mice (C57BL/6) who receive intracerebral injections of Theiler's Murine Encephalomyelitis Virus (TMEV) display acute spontaneous seizures several days after infection, survive the initial infection and go on to develop spontaneous recurrent seizures. Preliminary data using C57BL/6 mice with various cytokines or cytokine receptors knocked-out have shown that these genetic manipulations can significantly alter the pathologic sequelae observed following TMEV injection of wildtype mice. Therefore, we propose to test our overall hypothesis that TMEV infection is associated with increased expression of TNF-a that contributes to increased neuronal excitability, acute seizures, neuropathology, and ultimately, epilepsy. The proposed experiments will lead to a greater understanding of the role of viral and immune contributions to acute seizures, altered neuronal and glial function, and epileptogenesis. We will use a multidisciplinary approach;including, chronic video-EEG monitoring and brain slice electrophysiology to: 1) test the hypothesis that the TNF-a pathway plays an important role in the development of chronic seizures following TMEV infection, and 2) test the hypothesis that TNF-a signaling mediates changes in synaptic and/or glial function in the hippocampus in TMEV infected mice. We anticipate that the results generated will provide a novel model in which to study the role of infection in the development of epilepsy. In addition, these experiments will provide important new insight into the role of TNF-a in cell death, synaptic transmission and epileptogenesis and set the stage for the development of novel therapeutic interventions for the prevention of infection-induced epilepsy. PUBLIC HEALTH RELEVANCE: Viral infections of the central nervous system are associated with an increased risk for seizures, status epilepticus, and the development of chronic epilepsy. We have developed a novel mouse model of viral induced epilepsy using cortical injections of Theiler's Murine Encephalitis Virus (TMEV) to study epileptogenesis. The proposed multidisciplinary set of experiments will lead to a greater understanding of the role of viral and host immune contributions to acute seizures, altered neuronal function, and epileptogenesis.